Making Sense Out of the Biological Matrix of Bipolar Disorder

Philadelphia, PA, August 20, 2012 – The more that we
understand the brain, the more complex it becomes. The same can be
said about the genetics and neurobiology of psychiatric disorders.
For “Mendelian” disorders, like Huntington disease,
mutation of a single gene predictably produces a single clinical
disorder, following relatively simple genetic principals. Compared
to Mendelian disorders, understanding bipolar disorder has been
extremely challenging. Its biology is not well understood and its
genetics are complex.

In a new paper, Dr. Inti Pedroso and colleagues utilize an
integrative approach to probe the biology of bipolar disorder. They
combined the results of three genome-wide association studies,
which examined the association of common gene variants with bipolar
disorder throughout the genome, and a study of gene expression
patterns in post-mortem brain tissue from people who had been
diagnosed with bipolar disorder. The findings were analyzed within
the context of how brain proteins relate to each other based on the
Human Protein Reference Database protein-protein interaction
network.

“None of our research approaches provides us with
sufficient information, by itself, to understand the neurobiology
of psychiatric disorders. This innovative paper wrestles with this
challenge in a creative way that helps us to move forward in
thinking about the neurobiology of bipolar disorder,”
commented Dr. John Krystal, Editor of Biological Psychiatry.

Dr. Pedroso explained, “We combined information about
genetic variation from thousands of cases and controls with brain
gene expression data and information from protein databases to
identify networks of genes and proteins in the brain that are key
in the development of bipolar disorder.”

The analysis resulted in the ability to define risk gene
variants that were deemed functional, by virtue of the association
with changes in gene expression levels, and to group these
functional gene variants in biologically meaningful pathways.

The results implicated genes involved in several neural
signaling pathways, including the Notch and Wnt signaling pathways.
These pathways are key processes in neurotransmission and brain
development and these findings indicate they are also likely to be
involved in causing this severe disorder. The authors noted that
three features stand out among these genes: i) they localized to
the human postsynaptic density, which is crucial for neuronal
function; ii) their mouse knockouts present altered behavioral
phenotypes; and iii) some are known targets of the pharmacological
treatments for bipolar disorder.

Dr. Gerome Breen, senior author on the study and Senior Lecturer
at King's College London Institute of Psychiatry, said, “Our
study provides some of the first evidence to show the biochemical
and developmental processes involved in causing risk for developing
this life-long and costly illness. We have highlighted potential
new avenues for new drug treatments and intervention.”

Notes for editors
Full text of the article is available to credentialed journalists
upon request; contact Rhiannon Bugno at +1 214 648 0880 or
Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the
authors may contact Seil Collins at +44 0207 848 5377 or
seil.collins@kcl.ac.uk.

The authors’ affiliations, and disclosures of financial
and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of
Psychiatry at the Yale University School of Medicine and a research
psychiatrist at the VA Connecticut Healthcare System. His
disclosures of financial and conflicts of interests are available
here.

About Biological Psychiatry
Biological Psychiatry is the official journal of the Society of
Biological Psychiatry, whose purpose is to promote excellence in
scientific research and education in fields that investigate the
nature, causes, mechanisms and treatments of disorders of thought,
emotion, or behavior. In accord with this mission, this
peer-reviewed, rapid-publication, international journal publishes
both basic and clinical contributions from all disciplines and
research areas relevant to the pathophysiology and treatment of
major psychiatric disorders.

The journal publishes novel results of original research which
represent an important new lead or significant impact on the field,
particularly those addressing genetic and environmental risk
factors, neural circuitry and neurochemistry, and important new
therapeutic approaches. Reviews and commentaries that focus on
topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly
cited journals in the field of psychiatric neuroscience. It is
ranked 5th out of 129 Psychiatry titles and 16th out of 243
Neurosciences titles in the Journal Citations Reports®
published by Thomson Reuters. The 2011 Impact Factor score for
Biological Psychiatry is 8.283.

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